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Abstract

Introduction: Abdominal aortic aneurysm (AAA) is a common disease characterized by chronic inflammation and degradation of extracellular matrix. Integrin alpha1beta1 is a major collagen receptor that is expressed on activated monocytes and involved as well as smooth muscle cells and fibroblasts. The homeostatic chemokines, CCL19 and CCL21 and their receptor CCR7, have recently been linked to atherogenesis.

Purpose: We investigated the role of integrin alpha1beta1 using murine angiotensin II-induced AAA model in which alpha1 integrin was deficient.

Methods: Apolipoprotein E -/- mice that were either alpha1 +/+ or alpha1 -/-, were infused with either saline or angiotensin II (1000 ng/kg per minute) for 28 days via mini-osmotic pumps.

Results: Deficiency in integrin aplha1 tended to reduce the incidence of AAA (69% [alpha1 +/+] and 37% [alpha1 -/-], p= 0.12), but external diameters did not differ between the two groups; 1.6 ± 0.3 mm [alpha1 +/+] vs. 1.7 ± 0.7 mm [alpha1 -/-], p=NS, respectively). Interestingly, Kaplan-Meir survival curves revealed that the alpha1 -/- mice (n=36) were decreased in death due to aortic rupture compared to the alpha1 +/+ mice (n=36) (p=0.04). Zymography also showed the decrease in MMP-9 activity in aortae at day 7 in alpha1 -/- mice. Quantitative real time PCR showed that the decrease in TNF-alpha and the increase in collagen 1 expression in aortae at day 7 in alpha1 -/- mice. Of note, the increase in CCL21 at day 7 was significantly reduced in the alpha1-/- mice. In vitro experiments, CCL21 induced MMP9 from vascular smooth muscle cells.

Conclusions: Integrin alpha1beta1 is involved in susceptibility to aortic rupture in angiotensin II-induced AAA by the suppression of inflammation and the augmentation of collagen synthesis.